Conventional cancer diagnosis needs to excise diseased tissue from the patient's body for biopsy, causing severe injury to patients. Liquid biopsy with the superior advantage of minimal invasiveness has shown its ability to cancer diagnosis in real-time, and has been developing promising diagnostic instruments. However, until today, the developed instrument still cannot be an alternative to tissue biopsy in the majority of research and clinical settings. In this paper, we firstly summarize the challenges and limitations suffered by the existing liquid biopsy instrument. Then, the opportunities and future progression of the next-generation instrument are discussed in detail. In all, we hope that the future liquid biopsy instrument can be eventually integrated into the clinical workflow, and serve as a validated and reliable tool for cancer diagnosis.